Alzheimer's disease (AD) is a most widespread neurodegenerative pathology that affects one of four people over the age of 75 years. A specific neurodegenerative process developing in the memory-responsible brain structures underlies this disease. In spite of tremendous financial expenditures on research and symptomatic treatment of AD, it still remains incurable and eventually leads to death.
According to the World Health Organization, the prevalence of this disease is expected to increase with increasing total life expectancy in developed countries. Currently, there exist no effective means for AD prevention or essential retardation. Therefore, elucidation of the molecular mechanisms underlying AD development and search for effective treatment for this disease are vitally important problems.
According to clinical and epidemiological studies in representative groups of elderly people in Moscow, 4.5% of them have AD at the age of 60, their number growing with the age and reaching 15% at the age of 80 and beyond (Gavrilova, 2010 [RU]). The present strategy of AD therapy includes the following treatment modes: 1) compensatory (substitutive) therapy aimed to overcome neurotransmitter deficiency; 2) neuroprotective therapy which implies the use of neuroprotective agents and neurotrophic factors; correction of disturbance of free radical-involving events and calcium methabolism; the use of agents decreasing synthesis of [beta]-amyloid or causing its disaggregation, as well as metal-chelating agents; 3) immunotherapy against both [beta]-amyloid itself and the receptors mediating its neurotoxic effect; 4) the use of agents reducing hyperphosphorylation of the tau-protein or decreasing the level of cholesterol; 5) anti-inflammatory treatment; 6) hormonal treatment; 7) behavioral treatment including psychopharmacotherapy for productive psychopathological disorders and psychological correction (training) of cognitive functions (Bachurin et al., 2010 [RU], Stone et al., 2011).
Presently, AD treatment utilizes acetylcholinesterase inhibitors, agonists of muscarinic and nicotinic acetylcholine receptors, the agents promoting synthesis and accumulation of acetylcholine, which compensates deficiency of the acetyl cholinergic system, and neuroprotectors including calcium channel-blocking agents, NMDA-receptor antagonists (memantine), lazaroids (21-amino steroids), enzyme-blocking agents, stable analogs of endogenous neurotrophins and growth factors, peptidergic substances, and drugs based on brain-specific proteins (Gavrilova, 2002 [RU]). However, all these drugs provide only a delay in development of AD that remains incurable and lethal.
There are two forms of AD: sporadic and hereditary, the former being the most widespread and nine times more frequent than the latter. In recent years, more than ten various theories of AD etiology have been put forward. This disease can result from a combination of various factors that eventually lead to similar clinical and morphological pathologies. Basically, AD pathomorphology is represented by intra- and extracellular cerebral amyloidosis, neurofibrillary tangles, decreased synaptic density in the hippocampus, neuron death by apoptosis, and reactive astrogliosis (Bertoni-Freddari et al., 1996; Su et al., 1994). These morphological changes are of a mosaic nature and occur as sequential events in specific brain areas; their development correlates with the severity of cognitive impairment in patients with AD.
As shown by experiments on olfactory bulbectomized (OBX) animals, they develop a number of pathologies typical of AD, namely, (i) impairment of spatial memory; (ii) an increased level of [beta]-amyloid and formation of its plaque-like aggregates in the cerebral cortex, white matter, and hippocampus of guinea pigs whose [beta]-amyloid primary structure is identical to human one; (iii) dysfunction of the acetyl cholinergic system; (iv) neuron death in the AD-afflicted brain structures (the temporal cortex, hippocampus, and serotonin-synthesizing dorsal raphe nucleus of the brainstem); and (v) changes in the peripheral immune system similar to those observed in patients with AD (Bobkova et al., 2001, 2004, 2010 [RU], Bobkova et al., 2005; Nesterova et al., 2008).
Currently, the above is one of the most valid models of sporadic AD. It has been used, for example, to elucidate the effect of the heat shock protein Hsp70 on neurodegeneration. As follows from a variety of data, Hsp70 can produce a protective effect on mouse spatial memory. There exists an invention (WO 2013006076) describing intranasally administered Hsp70 as the means for treatment of neurodegenerative diseases. Along with the method of intranasal administering of Hsp70, the invention provides a therapeutically effective dose of Hsp70 and/or active fragment and/or derivative substance thereof.
Taking into account the difficulties of AD treatment, the list of existing therapeutically active agents should necessarily be extended. The technical result in the focus of the current invention is a method of the treatment of neurodegenerative diseases in mammals using the Y-box binding protein 1 (YB-1), and/or fragments and/or derivative thereof.